Cancer

Levels of Organization and Homeostasis

• Levels of organization (Biology flashback): Organism → Levels of Organization sequence left to right as presented:

  • Atom

  • Molecule

  • Macromolecule

  • Organelle

  • Cell

  • Tissue

  • Organ

  • Organ system

  • Organism

  • (Additional context from Page 2 reiterates these levels in a stair-step fashion)

• Homeostasis concept overview:

  • Homeostasis involves a stimulus detecting system changes and a feedback loop that maintains internal stability.

  • Core components (order as shown): Stimulus → Receptor/Sensor → Control Center → Effector → Response → Feedback Loop → Repeat as needed to restore balance.

  • When the levels or their interactions are disrupted, disease states can arise due to breakdowns at one or more organizational levels or their interconnections.

Homeostasis and Feedback Mechanics

• Homeostasis (detailed flow):

  • Stimulus triggers a receptor/sensor, which communicates to a control center.

  • The control center processes information and signals an effector to elicit a response.

  • The response yields feedback that modulates the stimulus, closing the loop.

• Key takeaway: stability arises from coordinated interaction among multiple organizational levels; disruption leads to disease.

Cellular Tasks and Organelles

• What cells do: diverse tasks via cellular differentiation.

• Eight key cellular functions (count = $8$):

  • Movement

  • Conductivity

  • Metabolic absorption

  • Secretion

  • Excretion

  • Respiration

  • Reproduction

  • Communication

• Major organelle functions:

  • Nucleus – cellular control center; contains DNA (the codebook for creating a human being).

  • Mitochondria – powerhouse; generates cellular energy via ATP.

  • Endoplasmic reticulum – protein management.

  • Golgi apparatus – packaging.

  • Ribosomes – translate RNA to proteins.

  • Lysosomes – contain degradative enzymes.

  • Cytoskeleton – provides structure and intracellular transport "roadways".

• Note: These organelles collectively support the eight cellular functions and overall cell health.

Cellular Metabolism: Aerobic vs Anaerobic

• Overview of energy pathways (as presented):

  • Aerobic respiration: Glycolysis → Pyruvic acid → Krebs cycle → Electron transport system (ETC) → ATP production.

  • Glycolysis yields energy (input: glucose; outputs: pyruvate, 2 ATP net in classic view, plus NADH).

  • Krebs cycle (citric acid cycle): Produces additional ATP precursors and reducing equivalents (NADH, FADH2).

  • Electron transport chain: Oxidative phosphorylation yields the majority of cellular ATP; final electron acceptor is O₂.

• Specific numerics shown in the transcript (as presented):

  • Krebs cycle output noted as $2 ext{ ATP}$ in the slide near “KREBS CYCLE”.

  • In the anaerobic section, the slide lists a number “$36 ext{ ATP}$” (likely reflecting total ATP from glycolysis + Krebs + ETC in some teaching resources; not a universal net).

  • Fermentation pathways (anaerobic) yield byproducts such as ethanol and lactate; observed outputs include NADH/NAD⁺ shifts and small ATP yields (as listed: 2x NAD, 2x ATP, etc.).

• Practical note: values shown reflect the slide’s content; standard textbooks may present different net ATP totals depending on pathway accounting.

DNA Function, Transcription, and Translation

• Function of DNA in controlling cell function:

  • Stable DNA molecule contains information for cell structure and function.

  • All cells contain the same genetic information; each cell type uses only a portion relevant to its function.

  • Four bases in DNA: $Adenine,<br>Cytosine,<br>Guanine,<br>Thymine$

  • In RNA, use $Uracil$ instead of Thymine.

• Transcription (DNA to RNA):

  • DNA serves as a template for RNA synthesis via RNA polymerase.

• Translation (RNA to proteins):

  • mRNA is translated by ribosomes using tRNA to assemble amino acids into polypeptide chains.

  • Example codon-to-amino acid mapping includes amino acids like Pro, Leu, Gly, Asn, Cys, etc.

• Protein formation and structure:

  • Proteins formed by translation have specific shapes; amino acid sequence determines structure.

  • 3–4 levels of protein structure; form dictates function.

  • Improperly formed proteins lead to altered function

DNA Mutations and Epigenetics

• DNA mutations and changes:

  • Types include substitutions, insertions/deletions, or rearrangements of base pairs.

  • Mutations can occur spontaneously or due to environmental agents (chemicals, radiation).

  • Can arise in somatic cells or germ cells; germ cell mutations can be inherited.

• Epigenetics and exposome (key concepts):

  • Epigenetic processes modify gene expression without changing DNA sequence (DNA methylation, histone modifications, non-coding RNA regulation, chromatin remodeling).

  • Exposome includes parental stress, nutrition, environmental chemicals/pollutants, microbiota, management practices, and environmental stress (e.g., heat/cold).

  • Epigenetic changes can affect phenotype (e.g., growth, disease resistance, production traits in animals) through regulation of gene expression.

Causes of Cellular Injury

• Mechanical injury

• Infectious agents

• Ischemic and hypoxic conditions

• Chemical and radiative injury

• Nutrient depletion

• Oxidative stress (free radicals/reactive oxygen species)

• These factors can act alone or in combination to disrupt cellular homeostasis.

Necrosis vs. Apoptosis

• Definitions:

  • Necrosis: uncontrolled, progressive cell injury with membrane breakdown, organelle/nucleus leakage, inflammation, and cellular fragmentation.

  • Apoptosis: programmed cell death with controlled degradation and phagocytosis of apoptotic bodies; typically non-inflammatory.

• Morphology (as shown):

  • Necrosis: membrane breakdown, amorphous densities, inflammatory response; often irreversible.

  • Apoptosis: membrane blebs, chromatin condensation, cell fragmentation, phagocytosis of apoptotic bodies.

• Recovery context: reversible injury may transition to necrosis if stress is not resolved; apoptosis is a controlled elimination process.

Cellular Adaptations

• Atrophy: decrease in cell size, leading to reduced tissue mass.

• Hypertrophy: increase in cell size, leading to enlarged tissue mass.

• Hyperplasia: increased cell number.

• Metaplasia: conversion of one mature cell type to another mature cell type.

• Dysplasia: variation in size/shape of cells within a tissue; disordered growth.

• Neoplasia: new, abnormal growth; commonly referred to as a tumor.

Cell Cycle, DNA Repair, and Cancer Foundations

• DNA repair mechanisms (brief):

  • Endonucleases recognize local distortions, remove distorted segments, DNA polymerase fills gaps using the intact strand as a template, and DNA ligase seals nicks.

  • Failure of repair can lead to mutations in proto-oncogenes and tumor suppressor genes, contributing to cancer development.

• Cancer basics:

  • Cancer is a cellular disease process characterized by abnormal growth and potential invasion, not simply a single tumor.

  • Invasive cancers can spread to other tissues (metastasis).

Historical Perspectives on Cancer

• Cancer has ancient references (Egyptian mummies/manuscripts).

• Early explanations blamed divine punishment, humoral imbalance, fermenting lymphatic fluid, and “blastema” theory.

Epidemiology and Cancer Burden (Illustrative figures from the slides)

• Deaths per 100,000 population by disease (illustrative):

  • Heart disease: $37.0$

  • Cancer: $138.8$

  • COVID-19: $236.4$

  • Unintentional injuries, stroke, chronic lower respiratory diseases, Alzheimer’s disease, diabetes, influenza/pneumonia, kidney disease, etc. (values shown on the chart for 2019 and 2020; exact numbers vary by category).

• Estimated new cancer cases (top sites, 2021 data excerpts):

  • Breast: $284{,}200$ new cases; Skin: $115{,}320$; Genital system: $376{,}970$; Digestive system: $338{,}090$; Respiratory system: numbers provided; Other/unspecified primary sites: $47{,}230$; etc.

• Estimated new cancer deaths (top sites, 2021 data excerpts):

  • Breast: $44{,}130$; Skin: data shown; Digestive system: $169{,}280$; Genital system: $69{,}110$; Respiratory system: $137{,}040$; Other sites: $47{,}230$; etc.

• Note: These figures illustrate the relative burden across sites and years; exact values are taken from the figures in the slides and should be interpreted as approximate.

Benign vs Malignant Tumors

• Features at a glance:

  • Growth rate: Benign grows slowly; Malignant grows rapidly.

  • Encapsulation: Benign is usually encapsulated and well-defined; Malignant is not encapsulated and invasive.

  • Invasiveness: Benign is non-invasive; Malignant is invasive and infiltrative.

  • Metastasis: Benign does not metastasize; Malignant can metastasize.

  • Differentiation: Benign cells are well differentiated; Malignant cells are poorly differentiated.

  • Mitotic index: Low in benign; High in malignant lesions.

Carcinogens and IARC Classifications

• IARC classifications (as presented):

  • Category 1: Carcinogenic to Humans

  • Category 2A: Probably Carcinogenic to Humans

  • Category 2B: Possibly Carcinogenic to Humans

  • Category 3: Not Classifiable as to Carcinogenicity in Humans

  • Category 4: Probably Not Carcinogenic

• Examples mentioned (selected from the slide):

  • Category 1 examples: Sunlight, Tobacco, Alcoholic beverages, Processed meat, Wood dust.

  • Category 2A: Nightshift work, Red meat, Glyphosate, High-temperature frying, etc.

  • Category 2B and Category 3 examples were listed variably in the slide (e.g., Aloe vera, Talc-based powders, etc.).

• Note: The slide lists several agents with IARC classifications and demonstrates the breadth of substances evaluated over time.

Biology of Cancer: Cellular Changes and Heterogeneity

• Carcinogenesis framework:

  • Malignant transformation: normal cell becomes a cancer cell through a series of genetic and epigenetic alterations.

  • Tumors are heterogeneous: cancer cells within a tumor can differ genetically and phenotypically; stroma and tumor microenvironment contribute to progression.

• Telomeres and immortality:

  • Telomeres shorten with each division; once critically short, normal cells undergo senescence.

  • Cancer cells often bypass senescence through telomere maintenance mechanisms, enabling continued division.

• Philadelphia chromosome example:

  • Translocation t(9;22) creates BCR-ABL fusion oncoprotein driving proliferation.

• Oncogenes and tumor suppressor genes (conceptual framework):

  • Proto-oncogenes, when mutated, become oncogenes that promote growth; tumor suppressor genes normally restrain growth and ensure cell-cycle control.

• The classic two-hit model (illustrated with analogies):

  • Tumor suppressor genes require inactivation of both alleles to lose function (two hits) and enable cancer progression.

  • Oncogenes typically need a single activating mutation (one hit) to promote uncontrolled growth.

  • Analogy: tumor suppressors = brakes; oncogenes = accelerators; cancer arises when brakes are released or accelerators are stuck.

Detailed Oncogene and Tumor Suppressor Concepts

• Proto-oncogenes vs oncogenes (table-style comparison):

  • Alleles mutated in cancer: Proto-oncogene (one) vs Tumor suppressor genes (two hits commonly needed)

  • Germ line transmission: rare for proto-oncogenes, more common for tumor suppressors in familial cancers

  • Somatic mutations: yes for both classes

  • Function of mutant allele: Proto-oncogene gains function (dominant); Tumor suppressor loses function (recessive)

  • Effects on cell growth: Proto-oncogenes promote growth; Tumor suppressors inhibit growth

  • Examples: Her2/neu, Ras, MYC (proto-oncogenes); BRCA1/BRCA2, p53, Rb (tumor suppressors)

• The two-hit hypothesis and daycare analogy:

  • Two hits needed for tumor suppressors (e.g., both alleles must be inactivated) to remove growth restriction.

  • Oncogenes may require only one activating mutation to drive growth.

Inflammation and Cancer Hallmarks

• Inflammation as a cancer-promoting factor:

  • Chronic inflammation supports carcinogenesis by sustaining a wound-healing-like environment, promoting proliferation and angiogenesis.

  • Inflammation helps cancer cells evade immune destruction and sustain growth.

• Hallmarks of cancer (as summarized in the slide adaptation):

  • Sustained proliferative signaling

  • Evading growth suppressors

  • Resisting cell death

  • Inducing angiogenesis

  • Enabling replicative immortality

  • Activating invasion and metastasis

  • Deregulating cellular energetics

  • Avoiding immune destruction

  • Genomic instability (mutator phenotype)

  • Tumor-promoting inflammation (supporting other hallmarks)

• These hallmarks provide a framework for understanding cancer biology and targets for therapy.

Cancer Progression and Metastasis

• Metastasis cascade (simplified):

  • Primary tumor experiences proliferation and stromal interaction

  • Local invasion into surrounding tissues

  • Intravasation into blood/lymphatic systems

  • Dissemination through circulation

  • Extravasation into distant tissues

  • Colonization and growth at distant sites (micrometastasis to macroscopic metastasis)

Clinical Manifestations and Complications of Cancer

• Common clinical manifestations:

  • Pain, anorexia and weight loss, fatigue, bleeding, bone metastases (pain, pathological fractures), brain metastases (falls, seizures), hypercoagulability, anemia, susceptibility to infection, jaundice (liver metastases), pneumonia (lung metastases), shortness of breath.

• Mass effect considerations:

  • Tumor mass can cause obstruction or compression of nearby structures (e.g., jaundice from bile ducts compression, abdominal masses, brain mass effect).

• Paraneoplastic syndromes:

  • Endocrinopathies (Cushing syndrome, SIADH), hypercalcemia, hypoglycemia, polycythemia, among others; mechanisms include ectopic hormone production, humoral factors, or metabolic dysregulation by tumor cells.

Cachexia and Nutritional Impact

• CACHEXIA: an extreme form of malnutrition characterized by hyper-catabolism and hypo-anabolism, leading to protein-calorie malnutrition and progressive wasting.

• Manifestations include anorexia, early satiety, weight loss, anemia, asthenia, taste alterations, and metabolic disturbances affecting proteins, lipids, and carbohydrates.

Cancer Staging and Clinical Assessment

• Staging framework (as described):

  • Stage I: confined to organ of origin

  • Stage II: locally invasive

  • Stage III: advanced to regional structures

  • Stage IV: spread to distant sites

Cancer Treatments and Therapeutic Modalities

• Treatment options overview:

  • Surgery: aims for complete removal with adequate margins; margins help determine subsequent therapy

  • Radiation therapy: targets cancer cells while minimizing damage to normal tissue; uses ionizing radiation to cause DNA damage; includes brachytherapy with implanted seeds

  • Chemotherapy: uses agents to kill fast-growing cells; includes antimetabolites, alkylating agents, vinca alkaloids, taxoids; works in cell cycle–specific or non-specific manners

  • Immunotherapy: harnesses the immune system to recognize and destroy cancer cells; can have fewer side effects on healthy tissues compared to traditional cytotoxic therapies

  • Stem cell transplant: supports recovery of healthy bone marrow after aggressive treatments

• Specifics on radiotherapy and chemotherapy:

  • Radiation damages DNA, leading to cancer cell death; normal tissue can be affected; total lifetime dose considerations exist.

  • Cell cycle–specific chemotherapy targets particular phases (e.g., S phase, M phase) and exploits checkpoints such as G1, intra-S, G2, and M with regulators like Cyclins and CDKs (e.g., Cyclin D/CDK4, Cyclin E/CDK2, Cyclin A/CDK2, Cyclin B/CDK1).

• Immunotherapy as future direction: emphasized as a therapy that activates patient’s immune system to target cancer with potentially fewer side effects on healthy tissue.

Practical and Educational Notes

• You may encounter the Philadelphia chromosome example (t(9;22) with BCR-ABL) as a classic demonstration of a specific genetic abnormality driving cancer progression.

• A daycare analogy is useful for conceptualizing how oncogenes (accelerators) and tumor suppressor genes (brakes) interact to regulate cell growth and how mutations can derail this balance.

• Historical and epidemiological data provide context for cancer burden and the importance of early detection, prevention, and tailored therapies.

Quick Reference: Key Terms to Remember

• Levels of organization: atom → molecule → macromolecule → organelle → cell → tissue → organ → organ system → organism.

• Homeostasis components: stimulus, receptor/sensor, control center, effector, response, feedback loop.

• Eight cellular functions: $8$ items listed above.

• DNA bases: $Adenine,<br>Cytosine,<br>Guanine,<br>Thymine$ (RNA uses $Uracil$).

• Protein structure levels: primary, secondary, tertiary, quaternary (implied by the “3–4 levels”).

• Cell cycle phases: $G1 <br>ightarrow S <br>ightarrow G2 <br>ightarrow M$ with checkpoints: G1, intra-S, G2, M; regulators: $Cyclin ext{ }D/CDK6, ext{ }Cyclin ext{ }E/CDK2, ext{ }Cyclin ext{ }A/CDK2, ext{ }Cyclin ext{ }B/CDK1.$

• Hallmarks of cancer (selected): sustained proliferative signaling, evading growth suppressors, resisting cell death, inducing angiogenesis, activating invasion and metastasis, enabling replicative immortality, deregulating cellular energetics, avoiding immune destruction, genomic instability, tumor-promoting inflammation.

• Staging levels: Stage I–IV as defined above.

• Carcinogen classifications (IARC): Category 1 (carcinogenic to humans), Category 2A (probably), Category 2B (possibly), Category 3 (not classifiable), Category 4 (probably not).

Note: This set of notes consolidates content from the provided transcript into a structured study guide with sections mirroring the sequence and emphasis of the slides. The LaTeX formatting is included for all numerical references and key quantitative concepts as requested.